The major objective of Project 2 is to establish a drug development program to identify and test active antiangiogenesis agents (AAAs) that will prevent neovascularization and thus recurrence of malignant gliomas. Dr. Paul Calabresi, who has been actively involved in drug development for many years, has established a firm collaboration with an international pharmaceutical company, Farmitalia Carlo Erba (FICE), based in Milan, Italy, to study novel AAAs synthesized in their laboratories. Distamycin A and suramin derivatives provided by FICE, as well as other related compounds synthesized by Dr. H. Chu in our Medicinal Chemistry core Laboratory, will be screened utilizing a unique in vitro capillary growth assay developed in Dr. Calabresi's laboratory. This model, which cocultures microvascular fragments and myofibroblasts, induces capillary growth easily and reproducibly. Active agents will be studied by Dr. Paul Finch, an extremely competent molecular biologist from NIH who has recently joined our group, to determine their site and mechanism of action. At the same time, Dr. Lars Wahlberg, a neurosurgeon with strong interests and training in bioengineering and polymer chemistry, will be preparing AAA-polymer controlled release delivery systems with active compounds. These polymeric systems will be studied in vitro and in vivo, using the nude mouse xenograft system and cell lines isolated by Dr. Ming Chu in Project 1. the pharmacokinetics of this slow release system will be measured by Dr. Darrell Abernethy, an experienced clinical pharmacologist, and his staff in the Clinical Pharmacology Core Laboratory. After determining preliminary preclinical toxicology of these polymeric-AAA systems, formal preclinical toxicology studies will be performed by the FICE Company in their laboratories in Milan, in order to obtain Investigational New Drug (IND) approval by the Food and Drug Administration (FDA). When FDA approval has been obtained, Phase I and Phase II clinical trials will be initiated by our group at Brown University and RIH as part of Project 4, described in this application.